The present invention relates to inhibitors of enzymes involved in the biosynthesis of sex steroids from natural precursors and to their use in the treatment of sex steroid dependent diseases. In particular, inhibitors are disclosed which suppress the activity of type 3 and type 5 17xcex2-hydroxysteroid dehydrogenase, thus diminishing the production of androgens catalyzed by these two enzymes. Pharmaceutical use of the inhibitors may reduce the natural production of androgens such as testosterone and dihydrotestosterone, and thereby beneficially treat diseases whose onset or progress is aided by androgenic activity. Because androgens formed by reactions catalyzed by type 3 or type 5 enzyme are precursors to estrogens, the invention also has applicability to diseases whose onset or progress is aided by estrogenic activity.
Many androgen-sensitive diseases, i.e. diseases whose onset or progress is aided by androgenic activity, are known. They include but are not limited to prostate cancer, benign prostatic hyperplasia, acne, seborrhea, hirsutism, androgenic alopecia, precocious puberty, adrenal hyperplasia, and polycystic ovarian syndrome. Estrogen sensitive diseases, i.e. diseases whose onset or progress is aided by estrogenic activity are also known. They include but are not limited to breast cancer, endometriosis, leiomyoma, and precocious puberty.
Precocious puberty is usually associated with an excess of androgen secretion, usually of adrenal origin. The current treatments include blockade of adrenal secretion by glucocorticoids with its associated side effects. Blockade of type 5 17xcex2-HSD would be an advantage, thus desirably reducing the dose or avoiding the use of glucocorticoids. Another treatment is the use of LHRH agonists to cause medical castration. A better controlled inhibition of androgen formation could be achieved with type 5 and 3 17xcex2-HSD inhibitors.
Polycystic ovarian syndrome is associated with an excess of androgen secretion by the ovaries. LHRH agonists are used among other, as treatment, to cause medical castration. The use of an inhibitor of 17xcex2-HSD would be advantageous.
Estrogen sensitive diseases may vary in their responses to androgens. They may, for example, respond favorably, unfavorably or not at all to androgens. Likewise, androgen-sensitive diseases may respond differently to estrogens. Thus, the treatment of sex steroid sensitive diseases may involve increasing or decreasing androgenic activity depending on whether the disease in question responds favorably or unfavorably to androgenic activity. Treatment may also involve increasing or decreasing estrogenic activity depending on whether the disease in question responds favorably or unfavorably to estrogenic activity. Breast cancer, for example, is known to respond favorably to androgenic activity and negatively to estrogenic activity. Benign prostatic hyperplasia is believed to respond negatively to both androgenic and estrogenic activity.
Androgenic and estrogenic activity may be suppressed by administering androgen receptor antagonists (xe2x80x9cantiandrogensxe2x80x9d) or estrogen receptor antagonists (xe2x80x9cantiestrogensxe2x80x9d), respectively. See e.g. WO 94/26767 and WO 96/26201. Androgenic and estrogenic activity may also be reduced by suppressing androgen or estrogen biosynthesis using inhibitors of enzymes that catalyze one or more steps of such biosynthesis or by suppressing ovarian or testicular secretions by known methods. See e.g. WO 90/10462, WO 91/00731, WO 91/00733, and WO 86/01105. Type 5 17xcex2-hydroxysteroid dehydrogenase is described in WO 97/11162.
Effective inhibitors of type 5 17xcex2-hydroxysteroid dehydrogenase enzyme are provided by the present invention. The prior art is not believed to have provided compounds sufficiently effective at simultaneously (1) inhibiting type 5 or type 3 17xcex2-hydroxysteroid dehydrogenase while (2) desirably failing to substantially inhibit other 17xcex2-hydroxysteroid dehydrogenases or other catalysts of sex steroid degradation. Medroxyprogesterone acetate, megestrol acetate, and chlormadinone acetate which the prior art as used as pharmaceutical agents for other purposes are not believed to have been disclosed as inhibitors of type 5 17xcex2-hydroxysteroid dehydrogenase, although applicants"" research has now shown them to inhibit that type 5 enzyme.
It is accordingly an object of the present invention to more selectively and effectively inhibit type 3 and/or type 5 17xcex2-hydroxysteroid dehydrogenase while preferably avoiding inhibition of other 17xcex2-hydroxysteroid dehydrogenases, type 1 or 2 3xcex1-hydroxysteroid dehydrogenases, or other androgen degradation enzymes.
It is another object to provide novel inhibitors of types 3 and 5 17xcex2-hydroxysteroid dehydrogenase and pharmaceutical compositions thereof.
It is another object to provide treatment and prevention regimens for androgen and estrogen sensitive diseases which regimens include inhibiting activity of type 3 or type 5 17xcex2-hydroxysteroid dehydrogenase.
In one embodiment, the invention provides a method of inhibiting activity of type 5 17xcex2-hydroxysteroid dehydrogenase comprising administering to a patient in need of such treatment a therapeutically effective amount of an inhibitor of type 5 17xcex2-hydroxysteroid dehydrogenase having the molecular structure: 
wherein the dotted line is optional pi bond;
wherein A is selected from the group consisting of straight or branched C1-C4 alkyl, xe2x80x94ORc (Rc being a C1-C8 alkyl radical), and xe2x80x94N(Rd)Re (Rd and Re being independently hydrogen or C1-C8 alkyl or aryl), and unsaturated analogs of any of the foregoing definitions for substituent A;
wherein R1 is selected from the group consisting of hydrogen and methyl;
wherein R6 is selected from the group consisting of hydrogen, and halogen, and C1-C8 alkyl;
wherein Ra is selected from the group consisting of straight or branched C1-C8 alkylene, C3-C7 cycloalkylene; and
Rb is selected from the group consisting of hydrogen, substituted or unsubstituted phenyl, C2-C10 acyl, C2-C10 acyloxy, C2-C10 alkoxycarbonyl, and halogen;
provided that when A is methyl, Ra and Rb together have at least two carbon atoms, and R1 is methyl.
It is preferred that the optional pi bond at 6 is present that R6 is methyl, that Ra is C1-C6 alkylene or that A is either methyl or xe2x80x94N(Rd)Re.
It is also preferred when wherein A is xe2x80x94N(Rd)Re that Rd is methyl or that Re is C1-C6 alkyl or C7-C12 phenyl alkyl.
In another embodiment, the invention provides a method of inhibiting activity of type 5 17xcex2-hydroxysteroid dehydrogenase comprising administering to a patient in need of such treatment a therapeutically effective amount of an inhibitor of type 5 17xcex2-hydroxysteroid dehydrogenase having the molecular structure: 
wherein the dotted line is an optional pi bond;
wherein R16xcex2 is selected from the group consisting of hydrogen, fluoro, chloro, C1-C8 alkyl, C1-C8 haloalkyl, a moiety which together with R16xcex1 is C4-C7 spirocycloalkyl, C4-C7 halospirocycloalkyl, or xe2x95x90xe2x80x94Rxe2x80x216 (Rxe2x80x216 being C1-C3 alkyl) and unsaturated analogs of any of the foregoing definitions of R16xcex2;
wherein R16xcex1 is selected from the group consisting of hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, a moiety which together with R16xcex2 forms C4-C7 spirocycloalkyl, C4-C7 halospirocycloalkyl, or xe2x95x90xe2x80x94Rxe2x80x216 (Rxe2x80x216 being C1-C3 alkyl) and unsaturated analogs of any of the foregoing.;
wherein R15xcex1 is selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkenyl and C1-C4 alkynyl;
wherein R19 is either xe2x80x94H or xe2x80x94CH3; and
wherein R6 is selected from the group consisting of xe2x80x94H, CH3, and halo;
provided that R16xcex2, R16xcex1, and R15xcex1 are not simultaneously hydrogen.
It is preferred that R16xcex1 is a larger substituent than R16xcex1, that R6 is hydrogen, that the optional pi bond at position 1 is not present or that R16xcex1 is a C3-C5 alkyl chain.
In another embodiment, the invention provides a method of inhibiting activity of type 5 17xcex2-hydroxysteroid dehydrogenase comprising administering to a patient in need of such treatment a therapeutically effective amount of an inhibitor of type 5 17xcex2-hydroxysteroid dehydrogenase having the molecular structure: 
wherein the dotted line is optional pi bond
wherein X is C1-C3 alkyl;
wherein Y is hydrogen or an acyloxy moiety;
wherein R6 is xe2x80x94H or xe2x80x94CH3;
wherein R16 is xe2x80x94H or halo;
wherein R1 is xe2x80x94H or xe2x80x94CH3.
It is preferred that R6 is methyl that the optional pi bond at position 1 is present, that Y is a C3-C6 fluoroacyloxy or that X is methyl.
In another embodiment, the invention provides a method of inhibiting activity of type 5 17xcex2-hydroxysteroid dehydrogenase comprising administering to a patient in need of such treatment a therapeutically effective amount of an inhibitor of type 5 17xcex2-hydroxysteroid dehydrogenase having the molecular structure: 
wherein n is an integer from 1-2;
wherein the dotted lines are optional double bonds;
wherein X and Y are independently selected from the group consisting of xe2x80x94H, (C1-C3)alkyl, (C2-C3)alkenyl, and methoxycarbonyl;
wherein Z is selected from the group consisting of xe2x80x94H and (C1-C3)alkyl;
wherein R3 is selected from the group consisting of hydrogen, acyl, carboxyl, alkoxycarbonyl, substituted or unsubstituted carboxamide, cyano, alkoxy, alkoxyalkoxy, alkythioalkoxy, acyloxy; hydroxy, halo, xe2x80x94Oxe2x80x94SO2Ra (Ra being selected from the group consisting of C1-C6 alkyl and C6-C10 aryl), and a moiety which, together with R2, is a 5-6 member ring containing at least one oxygen and one nitrogen atom;
wherein R2 is selected from the group consisting of hydrogen, amido, acyloxy, carboxyl, carboxamide, alkoxycarbonyl, cyano, halo, nitro, C1-C8 alkyl, and CF3 and a moiety which, together with R3, is a 5-6 member ring containing at least one oxygen and one nitrogen atom;
wherein R4 is hydrogen or halo;
wherein R6 is selected from the group consisting of hydrogen and oxo;
wherein R9 is xe2x80x94H or xe2x80x94OH;
provided that X, Y, and Z are not all hydrogens when R3 is methoxy.
It is preferred that R3 is alkoxyalkoxy, carboxamide, carboxyl or alkoxyl, that at least one of X, Y or Z is methyl, that both X and Y are methyl, that n is 1 or that R6 is oxo.
In another embodiment, the invention provides a method of inhibiting activity of type 5 17xcex2-hydroxysteroid dehydrogenase comprising administering to a patient in need of such treatment a therapeutically effective amount of an inhibitor of type 5 17xcex2-hydroxysteroid dehydrogenase having the molecular structure: 
wherein the dotted lines are optional pi bonds;
wherein n=1 or 2; and
wherein a is either xe2x80x94H or xe2x80x94CH3;
wherein b and c are independently hydrogen or methyl;
wherein Z is oxygen or sulfur.
It is preferred that n is 1, that at least one of b or c is methyl, both b and c are methyl or that Z is oxygen.
In another embodiment, the invention provides a method of inhibiting activity of type 5 17xcex2-hydroxysteroid dehydrogenase comprising administering to a patient in need of such treatment a therapeutically effective amount of an inhibitor of type 5 17xcex2-hydroxysteroid dehydrogenase selected from the group consisting of: 
It is preferred that the type 5 inhibitor is selected from the group consisting of: 
In another embodiment, the invention provides a method of inhibiting activity of type 5 17xcex2-hydroxysteroid dehydrogenase comprising administering to a patient in need of such treatment a therapeutically effective amount of an inhibitor of type 5 17xcex2-hydroxysteroid dehydrogenase selected from the group consisting of: 
and compounds having the molecular structure: 
wherein the dotted lines are optional pi bonds;
wherein A is selected from the group consisting of straight or branched C1-C4 alkyl, xe2x80x94ORc (Rc being a C1-C4 alkyl radical), and xe2x80x94N(Rd)Re (Rd and Re being independently hydrogen or C1-C8 alkyl or aryl), and unsaturated analogs of any of the foregoing definitions for substituent A;
wherein R1 is selected from the group consisting of hydrogens, and methyl;
wherein R6 is selected from the group consisting of hydrogen, halogen, and C1-C8 alkyl;
wherein R16 is selected from the group consisting of H,H and CH2;
wherein Ra is selected from the group consisting of straight or branched C1-C8 alkylene, C3-C7 cycloalkylene; and Rb is selected from the group consisting of hydrogen, substituted or unsubstituted phenyl, C2-C10 acyl, C2-C10 acyloxy, C2-C10 alkoxycarbonyl, and halogen.
In another embodiment, the invention provides a method of inhibiting activity of type 5 17xcex2-hydroxysteroid dehydrogenase comprising administering to a patient in need of such treatment a therapeutically effective amount of an inhibitor of type 5 17xcex2-hydroxysteroid dehydrogenase having the molecular structure: 
wherein the dotted line are optional pi bonds;
wherein R16xcex2 is selected from the group consisting of hydrogen, fluoro, chloro, C1-C8 alkyl, C1-C8 haloalkyl, a moiety which together with R16xcex1 forms C4-C7 spirocycloalkyl, C4-C7 halospirocycloalkyl, or xe2x95x90xe2x80x94Rxe2x80x216 (Rxe2x80x216 being C1-C3 alkyl) and unsaturated analogs of any of the foregoing definitions of R16xcex2;
wherein R16xcex1 is selected from the group consisting of hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, a moiety which together with R16xcex2 forms C4-C7 spirocycloalkyl C4-C7 halospirocycloalkyl, or xe2x95x90xe2x80x94Rxe2x80x216 (Rxe2x80x216 being C1-C3 alkyl) and unsaturated analogs of any of the foregoing;
wherein R15xcex1 is selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkenyl and C1-C4 alkynyl;
wherein R19 is either xe2x80x94H or CH3; and
wherein R6 is selected from the group consisting of xe2x80x94H, xe2x80x94CH3, and halo;
provided that R16xcex2, R16xcex1, and R15xcex1 are not simultaneously hydrogen.
In another embodiment, the invention provides a method of inhibiting activity of type 5 17xcex2-hydroxysteroid dehydrogenase comprising administering to a patient in need of such treatment a therapeutically effective amount of an inhibitor of type 5 17xcex2-hydroxysteroid dehydrogenase having the molecular structure: 
wherein n=1 or 2;
wherein the dotted lines are optional pi bonds;
wherein X and Y are independently selected from the group consisting of xe2x80x94H, (C1-C3)alkyl, (C2-C3)alkenyl, and methoxycarbonyl;
wherein Z is selected from the group consisting of xe2x80x94H and (C1-C3)alkyl;
wherein R3 is selected from the group consisting of acyl, carboxyl, alkoxycarbonyl, substituted or unsubstituted carboxamide, cyano, alkoxy, alkoxyalkoxy, alkythioalkoxy, acyloxy; hydroxy, halo, xe2x80x94Oxe2x80x94SO2Ra (Ra being selected from the group consisting of C1-C6 alkyl and C6-C10 aryl), and a moiety which, together with R2, is a 5-6 member ring containing at least one oxygen and one nitrogen atom;
wherein R2 is selected from the group consisting of amido, acyloxy, carboxyl, carboxamide, alkoxycarbonyl, cyano, halo, nitro, C1-C8 alkyl and CF3 and a moiety which, together with R3, is a 5-6 member ring containing at least one oxygen and one nitrogen atom;
wherein R4 is hydrogen or halo;
wherein R6 is selected from the group consisting of hydrogen and oxo;
wherein R9 is xe2x80x94H or xe2x80x94OH;
provided that X, Y, and Z are not hydrogens when R3 is methoxy.
It is preferred that R3 is alkoxyalkoxy, carboxamide, carboxyl or alkoxyl, that at least one of X, Y or Z is methyl, that both X and Y are methyl, that n is 1 or that R6 is oxo.
In another embodiment, the invention provides a method of inhibiting activity of type 5 17xcex2-hydroxysteroid dehydrogenase comprising administering to a patient in need of such treatment a therapeutically effective amount of an inhibitor of type 5 17xcex2-hydroxysteroid dehydrogenase having the molecular structure: 
wherein the dotted lines are optional pi bonds;
wherein n=1 or 2; and
wherein a is either xe2x80x94H or xe2x80x94CH3;
wherein b and c are independently hydrogen or methyl;
wherein Z is oxygen or sulfur.
In another embodiment, the invention provides a method of inhibiting activity of type 5 17xcex2-hydroxysteroid dehydrogenase comprising administering to a patient in need of such treatment a therapeutically effective amount of an inhibitor of type 5 17xcex2-hydroxysteroid dehydrogenase having the molecular structure: 
wherein the dotted line is an optional pi bond;
wherein A is selected from the group consisting of straight or branched C1-C4 alkyl, xe2x80x94ORc (Rc being a C1-C8 alkyl radical), and xe2x80x94N(Rd)Re (Rd and Re being independently hydrogen or C1-C8 alkyl or aryl), and unsaturated analogs of any of the foregoing definitions for substituent A;
wherein R1 is selected from the group consisting of hydrogen, methyl, and ethyl;
wherein R6 is selected from the group consisting of hydrogen, halogen, and C1-C8 alkyl;
wherein Ra is selected from the group consisting of straight or branched C1-C8 alkylene, C3-C7 cycloalkylene; and
Rb is selected from the group consisting of hydrogen, substituted or unsubstituted phenyl, C2-C10 acyl, C2-C10 acyloxy, C2-C10 alkoxycarbonyl, and halogen;
provided that when A is methyl, R1 is methyl.
In another embodiment, the invention provides a method of inhibiting activity of type 5 17xcex2-hydroxysteroid dehydrogenase comprising administering to a patient in need of such treatment a therapeutically effective amount of an inhibitor of type 5 17xcex2-hydroxysteroid dehydrogenase having the molecular structure: 
wherein the dotted lines are optional pi bonds
wherein X is C1-C3 alkyl;
wherein Y is hydrogen or an acyloxy moiety;
wherein R6 is xe2x80x94H or xe2x80x94CH3;
wherein R16 is xe2x80x94H or halo;
wherein R1 is xe2x80x94H or xe2x80x94CH3.
In another embodiment, the invention provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient, diluent or carrier and a therapeutically acceptable amount of an inhibitor of type 5 17xcex2-hydroxysteroid dehydrogenase having the molecular structure: 
wherein the dotted lines are optional pi bonds;
wherein A is selected from the group consisting of straight or branched C1-C4 alkyl, xe2x80x94ORc (Rc being a C1-C8 alkyl radical), and xe2x80x94N(Rd)Re (Rd and Re being independently hydrogen or C1-C8 alkyl or aryl), and unsaturated analogs of any of the foregoing definitions for substituent A;
wherein R1 is selected from the group consisting of hydrogen and methyl;
wherein R6 is selected from the group consisting of hydrogen, halogen, and C1-C8 alkyl;
wherein Ra is selected from the group consisting of straight or branched C1-C8 alkylene, C3-C7 cycloalkylene; and
Rb is selected from the group consisting of hydrogen, substituted or unsubstituted phenyl, C2-C10 acyl, C2-C10 acyloxy, C2-C10 alkoxycarbonyl, and halogen;
provided that when A is methyl, Ra and Rb together have at least two carbon atoms, and R1 is methyl.
It is preferred that the optional pi bond at 6 is present, that R6 is methyl, that Ra is C1-C6 alkylene or that A is either methyl or xe2x80x94N(Rd)Re.
It is also preferred when A is xe2x80x94N(Rd)Re, that Rd is methyl or that Re is C1-C6 alkyl or phenyl C1-C6 alkyl.
In another embodiment, the invention provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient, diluent or carrier and a therapeutically acceptable amount of an inhibitor of type 5 17xcex2-hydroxysteroid dehydrogenase having the molecular structure: 
wherein the dotted line is an optional pi bond;
wherein R16xcex2 is selected from the group consisting of hydrogen, fluoro, chloro, C1-C8 alkyl, C1-C8 haloalkyl, a moiety which together with R16xcex1 is C4-C7 spirocycloalkyl, C4-C7 halospirocycloalkyl, or xe2x95x90xe2x80x94Rxe2x80x216 (Rxe2x80x216 being C1-C3 alkyl) and unsaturated analogs of any of the foregoing definitions of R16xcex2;
wherein R16xcex1 is selected from the group consisting of hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, a moiety which together with R16xcex2 forms C4-C7 spirocycloalkyl, C4-C7 halospirocycloalkyl, or xe2x95x90xe2x80x94Rxe2x80x216 (Rxe2x80x216 being C1-C3 alkyl) and unsaturated analogs of any of the foregoings;
wherein R15xcex1 is selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkenyl and C1-C4 alkynyl;
wherein R19 is either xe2x80x94H or xe2x80x94CH3; and
wherein R6 is selected from the group consisting of xe2x80x94H, xe2x80x94CH3, and halo;
provided that R16xcex2, R16xcex1, and R15xcex1 are not simultaneously hydrogen.
It is preferred that R16xcex1 is a larger substituent than R16xcex2 that R6 is hydrogen, that the optional pi bond at position 1 is not present or that R16xcex1 is a C3-C5 alkyl chain.
In another embodiment, the invention provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient, diluent or carrier and a therapeutically acceptable amount of an inhibitor of type 5 17xcex2-hydroxysteroid dehydrogenase having the molecular structure: 
wherein the dotted line is an optional pi bond
wherein X is C1-C3 alkyl;
wherein Y is hydrogen or an acyloxy moiety;
wherein R6 is xe2x80x94H or xe2x80x94CH3;
wherein R16 is xe2x80x94H or halo;
wherein R1 is xe2x80x94H or xe2x80x94CH3.
It is preferred that R6 is methyl, that the optional pi bond at position 1 is present, that Y is a C3-C6 fluoroacyloxy or that X is methyl.
In another embodiment, the invention provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient, diluent or carrier and a therapeutically acceptable amount of an inhibitor of type 5 17xcex2-hydroxysteroid dehydrogenase having the molecular structure: 
wherein n is an integer from 1-2;
wherein the dotted lines are optional pi bonds;
wherein X and Y are independently selected from the group consisting of xe2x80x94H, (C1-C3)alkyl, (C2-C3)alkenyl, and methoxycarbonyl;
wherein Z is selected from the group consisting of xe2x80x94H and (C1-C3)alkyl;
wherein R3 is selected from the group consisting of hydrogen, acyl, carboxyl, alkoxycarbonyl, substituted or unsubstituted carboxamide, cyano, alkoxy, alkoxyalkoxy, alkythioalkoxy, acyloxy; hydroxy, halo, xe2x80x94Oxe2x80x94SO2Ra (Ra being selected from the group consisting of C1-C6 alkyl and C6-C10 aryl), and a moiety which, together with R2, is a 5-6 member ring containing at least one oxygen and one nitrogen atom;
wherein R2 is selected from the group consisting of hydrogen, amido, acyloxy, carboxyl, carboxamide, alkoxycarbonyl, cyano, halo, nitro, C1-C8 alkyl, and CF3 and a moiety which, together with R3, is a 5-6 member ring containing at least one oxygen and one nitrogen atom;
wherein R4 is hydrogen or halo;
wherein R6 is selected from the group consisting of hydrogen and oxo;
wherein R9 is xe2x80x94H or xe2x80x94OH;
provided that X, Y, and Z are not all hydrogen when R3 is methoxy.
It is preferred that R3 is alkoxyalkoxy, carboxamide, carboxyl or alkoxyl, that at least one of X, Y or Z is methyl, that both X and Y are methyl, that n is 1 or that R6 is oxo.
In another embodiment, the invention provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient, diluent or carrier and a therapeutically acceptable amount of an inhibitor of type 5 17xcex2-hydroxysteroid dehydrogenase having the molecular structure: 
wherein the dotted lines are optional pi bonds;
wherein n=1 or 2; and
wherein a is either xe2x80x94H or xe2x80x94CH3;
wherein b and c are independently hydrogen or methyl;
wherein Z is oxygen or sulfur.
It is preferred that n is 1, that at least one of b or c is methyl, that both b and c are methyl or that Z is oxygen.
In another embodiment, the invention provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient, diluent or carrier and a therapeutically acceptable amount of an inhibitor of type 5 17xcex2-hydroxysteroid dehydrogenase having a molecular structure selected from the group consisting of: 
It is preferred that the type 5 inhibitor is selected from the group consisting of: 
In another embodiment, the invention provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient, diluent or carrier and a therapeutically acceptable amount of an inhibitor of type 5 17xcex2-hydroxysteroid dehydrogenase having the molecular structure: 
wherein the dotted line is an optional pi bond;
wherein A is selected from the group consisting of straight or branched C1-C4 alkyl, xe2x80x94ORc (Rc being a C1-C8 alkyl radical), and xe2x80x94N(Rd)Re (Rd and Re being independently hydrogen or C1-C8 alkyl or aryl), and unsaturated analogs of any of the foregoing definitions for substituent A;
wherein R1 is selected from the group consisting of hydrogen and methyl;
wherein R6 is selected from the group consisting of hydrogen, and halogen, and C1-C8 alkyl;
wherein Ra is selected from the group consisting of straight or branched C1-C8 alkylene, C3-C7cycloalkylene; and
Rb is selected from the group consisting of hydrogen, substituted or unsubstituted phenyl, C2-C10 acyl, C2-C10 acyloxy, C2-C10 alkoxycarbonyl, and halogen;
provided that when A is methyl, R1 is methyl or ethyl.
In another embodiment, the invention provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient, diluent or carrier and a therapeutically acceptable amount of an inhibitor of type 5 17xcex2-hydroxysteroid dehydrogenase having the molecular structure: 
wherein the dotted lines are optional pi bonds
wherein X is C1-C3 alkyl;
wherein Y is hydrogen or an acyloxy moiety;
wherein R6 is xe2x80x94H or xe2x80x94CH3;
wherein R16 is xe2x80x94H or halo;
wherein R1 is xe2x80x94H or xe2x80x94CH3.
In another embodiment, the invention provides an inhibitor of type 5 17xcex2-hydroxysteroid dehydrogenase having the molecular structure: 
wherein the dotted line is optional pi bond;
wherein A is selected from the group consisting of straight or branched C1-C4 alkyl, xe2x80x94ORc (Rc being a C1-C8 alkyl radical), and xe2x80x94N(Rd)Re (Rd and Re being independently hydrogen or C1-C8 alkyl or aryl), and unsaturated analogs of any of the foregoing definitions for substituent A,
wherein R1 is selected from the group consisting of hydrogen and methyl;
wherein R6 is selected from the group consisting of hydrogen, and halogen, and C1-C8 alkyl;
wherein Ra is selected from the group consisting of straight or branched C1-C8 alkylene, C3-C7 cycloalkylene; and
Rb is selected from the group consisting of hydrogen, substituted or unsubstituted phenyl, C2-C10 acyl, C2-C10 acyloxy, C2-C10 alkoxycarbonyl, and halogen;
provided that when A is methyl, Ra and Rb together have at least two carbon atoms, and R1 is methyl.
It is preferred that the optional pi bond at 6 is present, that R6 is methyl; or that Ra is C1-C6 alkylene.
It is preferred that A is either methyl or xe2x80x94N(Rd)Re.
It is also preferred when A is N(Rd)Re, that Rd is methyl or that Re is C1-C6 alkyl or phenyl C1-C6 alkyl.
In another embodiment, the invention provides an inhibitor of type 5 17xcex2-hydroxysteroid dehydrogenase having the molecular structure: 
wherein the dotted line is an optional pi bond;
wherein R16xcex2 is selected from the group consisting of hydrogen, fluoro, chloro, C1-C8 alkyl, C1-C8 haloalkyl, a moiety which together with R16xcex1 is C4-C7 spirocycloalkyl, C4-C7 halospirocycloalkyl, or xe2x95x90xe2x80x94Rxe2x80x216 (Rxe2x80x216 being C1-C3 alkyl) and unsaturated analogs of any of the foregoing definitions of R16xcex2;
wherein R16xcex1 is selected from the group consisting of hydrogen, C1-C8 alkyl, C1-C8 haloalkyl and a moiety which together with R16xcex2 forms C4-C7 spirocycloalkyl, C4-C7 halospirocycloalkyl, or xe2x95x90xe2x80x94Rxe2x80x216 (Rxe2x80x216 being C1-C3 alkyl) and unsaturated analogs of any of the foregoings;
wherein R15xcex1 is selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkenyl and C1-C4 alkynyl;
wherein R19 is either xe2x80x94H or xe2x80x94CH3; and
wherein R6 is selected from the group consisting of xe2x80x94H, xe2x80x94CH3, and halo;
provided that R16xcex2, R16xcex1, and R15xcex1 are not simultaneously hydrogen.
It is preferred that R16xcex1 is a larger substituent than R16xcex2, that R6 is hydrogen, that the optional pi bond at position 1 is not present or that R16xcex1 is a C3-C5 alkyl chain.
In another embodiment, the invention provides an inhibitor of type 5 17xcex2-hydroxysteroid dehydrogenase having the molecular structure: 
wherein the dotted line is optional pi bond
wherein X is C1-C3 alkyl;
wherein Y is hydrogen or an acyloxy moiety;
wherein R6 is xe2x80x94H or xe2x80x94CH3;
wherein R16 is xe2x80x94H or halo;
wherein Rxe2x80x2is xe2x80x94H or xe2x80x94CH3.
It is preferred that R6 is methyl that the optional pi bond at position 1 is present, that Y is a C3-C6 fluoroacyloxy or that X is methyl.
In another embodiment, the invention provides an inhibitor of type 5 17xcex2-hydroxysteroid dehydrogenase having the molecular structure: 
wherein n is an integer from 1-2;
wherein the dotted lines are optional pi bonds;
wherein X and Y are independently selected from the group consisting of xe2x80x94H, (C1-C3)alkyl, (C2-C3)alkenyl, and methoxycarbonyl;
wherein Z is selected from the group consisting of xe2x80x94H and (C1-C3)alkyl;
wherein R3 is selected from the group consisting of hydrogen, acyl, carboxyl, alkoxycarbonyl, substituted or unsubstituted carboxamide, cyano, alkoxy, alkoxyalkoxy, alkythioalkoxy, acyloxy; hydroxy, halo, xe2x80x94Oxe2x80x94SO2Ra (Ra being selected from the group consisting of C1-C6 alkyl and C6-C10 aryl), and a moiety which, together with R2, is a 5-6 member ring containing at least one oxygen and one nitrogen atom;
wherein R2 is selected from the group consisting of hydrogen, amido, acyloxy, carboxyl, carboxamide, alkoxycarbonyl, cyano, halo, nitro, C1-C8 alkyl, and CF3 and a moiety which, together with R3, is a 5-6 member ring containing at least one oxygen and one nitrogen atom;
wherein R4 is hydrogen or halo;
wherein R6 is selected from the group consisting of hydrogen and oxo;
wherein R9 is xe2x80x94H or xe2x80x94OH;
provided that X, Y, and Z are not hydrogen when R3 is methoxy.
It is preferred that R3 is alkoxyalkoxy; carboxamide, carboxyl or alkoxyl, that at least one of X, Y or Z is methyl, that X and Y are methyl, that n is 1 or R6 is oxo.
In another embodiment, the invention provides an inhibitor of type 5 17xcex2-hydroxysteroid dehydrogenase having the molecular structure: 
wherein the dotted lines are optional pi bonds;
wherein n=1 or 2; and
wherein a is either xe2x80x94H or xe2x80x94CH3;
wherein b and c are independently hydrogen or methyl;
wherein Z is oxygen or sulfur.
It is preferred that n is 1, that at least one of b or c is methyl, that both b and c are methyl or that Z is oxygen.
In another embodiment, the invention provides an inhibitor of type 5 17xcex2-hydroxysteroid dehydrogenase having a molecular structure selected from the group consisting of: 
It is preferred that the type 5 inhibitor is selected from the group consisting of: 
In another embodiment, the invention provides a method of inhibiting type 3 17xcex2-hydroxysteroid dehydrogenase comprising administering to a patient in need of such treatment a therapeutically effective amount of an inhibitor of type 3 17xcex2-hydroxysteroid dehydrogenase having the molecular structure: 
wherein R is selected from the group consisting of alkoxy, alkylthio, alkoxyalkoxy, alkoxyalkylthio, alkylthioalkoxy, and alkylthioalkylthio, 
xe2x80x83wherein n is an integer from 1 to 4.
It is preferred that the said type 3 inhibitor is selected from the group consisting of: 
In another embodiment, the invention provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient, diluent or carrier and a therapeutically acceptable amount of an inhibitor of type 3 17xcex2-hydroxysteroid dehydrogenase having the molecular structure: 
wherein R is selected from the group consisting of alkoxy, alkylthio, alkoxyalkoxy, alkoxyalkylthio, alkylthioalkoxy, and alkylthioalkylthio,
or 
xe2x80x83wherein n is an integer from 1 to 4.
It is preferred that the said type 3 inhibitor is selected from the group consisting of: 
In another embodiment, the invention provides an inhibitor of type 3 17xcex2-hydroxysteroid dehydrogenase having the molecular structure: 
wherein R is selected from the group consisting of alkoxyethoxy, alkoxyalkylthio, alkylthioalkoxy, and alkylthioalkylthio,
or 
xe2x80x83wherein n is an integer from 1 to 4.
It is preferred that the said type 3 inhibitor is selected from the group consisting of: 
A patient in need of treatment or reducing the risk of onset of a given disease is one who has either been diagnosed with such disease or one who is particularly susceptible to acquiring such disease, for example, one at higher risk of acquiring the disease than the general population.
Except where otherwise stated, the preferred dosage of the active compounds of the invention is identical for both therapeutic and prophylactic purposes. The dosage for each active component discussed herein is the same regardless of the disease being treated (or prevented).
As used in the methods of medical treatment or methods of reduction of risk of onset of disease herein, an xe2x80x9cinhibitor of type 5 or 3 17xcex2-hydroxysteroid dehydrogenasexe2x80x9d means a compound whose IC50 of inhibition for the enzyme in question (computed in the same manner as described in connection with Table 1 herein) is no higher than 500 nM. It is preferred that such inhibitor be no higher than 20 nM, most preferably lower than 10 nM. In some embodiments of the type 5 or type 3 inhibitor, it is also preferred that IC50 of undesirable inhibition of type 2 17xcex2-hydroxysteroid dehydrogenase be more than 5 times that for inhibition of type 5, preferably more than 10 times, and most preferably more than 25 times. In some embodiments, it is preferred that the percentage of inhibition of the binding of [3H]R1881 on the androgen receptor (as described in D-Androgen Receptor (AR) assays, supra), by the inhibitor of type 5 or 3 17xcex2-hydroxysteroid dehydrogenase at the concentration of 10xe2x88x926 M be less than 30% most preferably less than 20%.
Where two or more different active agents are discussed as part of a combination therapy herein (e.g. an enzyme inhibitor and an antiandrogen), a plurality of different compounds are administered rather than a single compound having multiple activities.
Except where otherwise noted or where apparent from context, dosages herein refer to weight of active compounds unaffected by pharmaceutical excipients, diluents, carriers or other ingredients, although such additional ingredients are desirably included, as shown in the examples herein. Any dosage form (capsule, tablet, injection or the like) commonly used in the pharmaceutical industry, is appropriate for use herein, and the terms xe2x80x9cingredientxe2x80x9d, xe2x80x9cdiluentxe2x80x9d or xe2x80x9ccarrierxe2x80x9d include such non active ingredients as are typically, included together with active ingredients, used in such dosage form in the industry.